This invention relates to pharmaceutically useful compounds, processes for their production, pharmaceutical compositions containing them and methods of treatment involving their use.
T-cells play an important role in the immune response, however in autoimmune disease T-cells are activated against particular tissues, e.g. causing the inflammation associated with rheumatoid arthritis. Interleukin-2 (IL-2) is an essential autocrine growth factor for T-cells and hence inhibition of IL-2 transcription is beneficial in the modulation of autoimmune disease. Formation of a transcriptional complex of the protein nuclear factor of activated T-cells-1 (NFAT-1) on the IL-2 promoter is essential for IL-2 transcription. NFAT-1 mediated transcription has therefore been proposed as appropriate molecular target for immunomodulation, Y. Baine et al., J. Immunol., 1995, 154, 3667-3677.
W. F. Michne et al., in J. Med. Chem. (1995) 38, 2557-2569 disclose a number of quinazoline-2,4-diones and pyrrolo[3,4-d]pyrimidine-2,4-diones which inhibit transcription regulated by the DNA region bound by the NFAT-1 protein.
We have now found novel thieno[2,3-d]pyrimidinediones which exhibit pharmacological activity, in particular immunosuppressive activity.
In a first aspect the invention therefore provides a compound of formula (I): 
wherein:
R is xe2x80x94C(O)Ar1, xe2x80x94C(R4)(R5)Ar1, or Ar2;
Ar1 is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which can be optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl, or Ar1 is phenyl optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, xe2x80x94CH2N(R6)2, xe2x80x94NHSO2CF3, C1-4alkylsulphonylamino, xe2x80x94NHC(O)R6a, CO2R7 or xe2x80x94C(O)NR8R8a;
R4represents H or C1-4 alkyl;
R5represents H or OH;
each R6 independently represents H or C1-4 alkyl, preferably methyl or ethyl;
R6a represents H, C1-6 alkyl, aryl or arC1-4alkyl, wherein the aryl group or aryl moiety in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, C1-4 alkylcarbonylamino, halogen or trifluoromethyl;
R7 represents H or C1-4 alkyl, preferably methyl or ethyl;
R8 and R8a each independently represent H, C1-4 alkyl, preferably methyl or ethyl, phenyl or pyridyl;
Ar2 is acenaphthenyl, indanyl, iminodihydrobenzofuranyl or fluorenyl, each of which can be optionally substituted by one or more substituents selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen, or trifluoromethyl;
R1 and R2 are independently H, C1-6 alkyl, C3-6 alkenyl, CH2C3-5 cycloalkyl or C3-6 cycloalkyl;
R3 represents H, Xxe2x80x94R9 or Xxe2x80x94Ar3;
X represents S(O)n, C(O)NR10, C(O)O, NH(CO)NR10, NH(CO)O or SO2NR10;
n is 0, 1 or 2;
R9 represents a methyl group optionally substituted by one or more substituents selected from CN, CO2H, C1-5 alkoxycarbonyl, 5-tetrazolyl, SO2NH2 or C(O)NR11R12, or R9 represents C2-6 alkyl or C3-6 alkenyl, each of which may be optionally substituted by one or more substituents selected from OH, CN, CO2H, C1-5 alkoxy, C1-5 alkoxycarbonyl, 5-tetrazolyl, azide, phthalimido, SO2NH2, C(O)NR11R12, NR13R14, NHC(O)R15 or NHSO2R16 where R11, R12, R13 and R14 each independently represent H or C1-4 alkyl,
R15 represents C1-4 alkyl, C1-4 alkoxy, di(C1-4alkyl)amino, or alkoxyalkylene containing up to 6 carbon atoms, and R16 represents C1-4 alkyl or trifluoromethyl; or, additionally, in the case where X represents C(O)NR10, NH(CO)NR10 or SO2NR10, R9 and R10 together with the nitrogen atom to which they are attached may form a 4- to 7-membered heterocyclic ring which may be optionally substituted by one or more OH groups;
R10 represents H, C1-6 alkyl or is linked to R9 as defined above; and
Ar3 is phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one or more substituents selected from OH, NO2, NH2, NHSO2CF3, C1-4 alkoxy, bis-C1-4alkanesulphonylanino, C1-4alkylcarbonylamino or C1-4alkoxycarbonylamino; or a pharmaceutically-acceptable salt or solvate thereof.
In the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched. Where a substituent in an alkenyl group is OH, phthalimido, NR13R14 or NHC(O)R15, the substituent is not attached to an unsaturated carbon atom. The alkyl moieties in a di(C1-4 alkyl)amino group may be the same or different.
The group R is xe2x80x94C(O)Ar1, xe2x80x94C(R4)(R5)Ar1, or Ar2.
The group R4 represents H or C1-4 alkyl, preferably methyl or ethyl, and the group represents H or OH.
Preferably Ar1 is naphthyl, quinolyl, isoquinolyl, indolyl, benzofuranyl or benzothienyl, each of which can be optionally substituted by one to four, particularly one or two, substituents selected from C1-4 alkyl (e.g. methyl or ethyl), C1-4 alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine) or trifluoromethyl, or Ar1 is phenyl optionally substituted by one to four, particularly one or two, substituents selected from C1-4 alkyl (e.g. methyl or ethyl), C1-4 alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, amino, nitro, cyano, trifluoromethoxy, phenoxy, xe2x80x94CH2N(R6)2, xe2x80x94NHSO2CF3, C1-4alkylsulphonylamino, xe2x80x94NHC(O)R6a, CO2R7 or xe2x80x94C(O)NR8R8a.
Most preferably Ar1 is naphthyl, quinolyl or benzofuranyl, or a phenyl group optionally substituted by one or two substituents selected from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, nitro, amino, cyano, phenoxy or xe2x80x94NHC(O)R6a.
The group Ar2 is preferably acenaphthenyl, indanyl, iminodihydrobenzofuranyl or fluorenyl, each of which can be optionally substituted by one to four, particularly one or two, substituents selected from OH, C1-4 alkyl (e.g. methyl or ethyl), C1-4 alkoxy (e.g. methoxy or ethoxy), halogen (e.g. fluorine, chlorine or bromine) or trifluoromethyl. Especially preferred are indanyl, iminodihydrobenzofuranyl and hydroxy-substituted indanyl groups.
R6a is preferably H, C1-6, particularly C1-4, alkyl, aryl or arC1-4alkyl, wherein the aryl group or aryl moiety in the aralkyl group is phenyl or pyridyl, each of which may be optionally substituted by one to four, especially one or two, substituents selected from C1-4 alkyl (e.g. methyl or ethyl), C1-4 alkoxy (e.g. methoxy or ethoxy), C1-4 alkylcarbonylamino (e.g. methyl- or ethylcarbonylamino), halogen (e.g. fluorine, chlorine or bromine) or trifluoromethyl.
Most preferably, R6a represents a phenyl or phenylC1-4alkyl group substituted in the aromatic ring by one or two substituents selected from methoxy and methylcarbonylamino.
Preferably R1 and R2 are independently H, C1-4 alkyl, C3-4 alkenyl or C3-6 cycloalkyl.
It is preferred that R1 is C3-4 alkyl or C4 alkenyl, in particular 1-methylethyl, 2-methylpropyl or 2-methylpropenyl.
It is preferred that R2 is H or, especially, methyl.
R3 represents H, Xxe2x80x94R9 or Xxe2x80x94Ar3.
X represents S(O)n where n is 0, 1 or 2, C(O)NR10, C(O)O, NH(CO)NR10, NH(CO)O or SO2NR10.
Preferably R9 represents a methyl group optionally substituted by CN, CO2H, C1-5 alkoxycarbonyl, 5-tetrazolyl, SO2NH2 or C(O)NR11R12, or R9 preferably represents C2-6 alkyl or C3-6 alkenyl, each of which may be optionally substituted by one to four, particularly one or two, substituents selected from OH, CN, CO2H, C1-5 alkoxy, C1-5 alkoxycarbonyl, 5-tetrazolyl, azide, phthalimido, SO2NH2, C(O)NR11R12, NR13R14, NHC(O)R15 or NHSO2R16 where R11, R12, R13 and R14 each independently represent H or C1-4 alkyl, particularly methyl or ethyl, R15 represents C1-4 alkyl, particularly methyl or ethyl, C1-4 alkoxy, particularly methoxy or ethoxy, di(C1-4alkyl)amino, particularly dimethylamino or diethylamino, or alkoxyalkylene containing from 2 to 4 carbon atoms, and R16 represents C1-4 alkyl, preferably methyl or ethyl, or trifluoromethyl; or, additionally, in the case where X represents C(O)NR10, NH(CO)NR10 or SO2NR10, R9 and R10 together with the nitroen atom to which they are attached may form a 5- or 6-membered heterocyclic ring which may be optionally substituted by one or two OH groups.
More preferably R9 represents a methyl group optionally substituted by CO2H or C(O)NR11R12, or a C2-4 alkyl group (e.g. ethyl, propyl or butyl) which may be optionally substituted by one or two substituents selected from OH, CO2H, C1-5 alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), azide, phthalimido, NR13R14, NHC(O)R15 or NHSO2R16; or R9 and R10 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring which may be optionally substituted by an OH group.
Preferably, R10 represents H, C1-2 alkyl, especially methyl, or is linked to R9 as defined above.
Most preferably, each of R11, R12, R13 and R14 represents hydrogen.
Most preferably, R15 represents methyl, methoxy, dimethylamino or methoxymethylene.
Most preferably, R16 represents methyl or trifluoromethyl.
Preferably, Ar3 is phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one to four, particularly one or two, substituents selected from OH, NO2, NH2, NHSO2CF3, C1-4 alkoxy (particularly methoxy or ethoxy), bis-C1-4alkanesulphonylamino (particularly bis-C2-4 alkanesulphonylamino), C1-4alkylcarbonylamino (particularly C1-2alkylcarbonylamino) or C1-4alkoxycarbonylamino (particularly C1-2alkoxycarbonylamino).
The group Ar3 is very preferably phenyl, pyridyl or pyridine N-oxide, each of which may be optionally substituted by one or two substituents selected from OH, NO2, NH2, methoxy, bis-methanesulphonylamino, methylcarbonylamino or methoxycarbonylamino.
Particularly preferred compounds of the invention include:
6-(4-Methoxyphenylmethyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-(4-Methoxyphenylmethyl)-3-methyl-1-(2-methyl-2-propenyl)thieno[2,3-d]-pyrimidine-2,4(1H,3H)-dione,
1-(2-Methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(2-pyridinyl)-thio]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
5-[(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
Methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoate,
4-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]butanoic acid,
Methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfinyl]butanoate,
Methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoate,
4-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoic acid,
6-Benzyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
3-Methyl-1-(1-methylethyl)-6-(phenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-[(1-Hydroxy-1-phenyl)methyl]-3-methyl-1-(2-methylpropl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
(xc2x1) 5-[(2-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylnethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,
(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylnethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidin-3-ol,
1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}piperidin-4-ol,
(3R)-1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}piperidin-3-ol,
1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3,N-dimethyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,
2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}acetic acid,
3-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}propanoic acid,
2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carboxamido}acetamide,
1-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl}pyrrolidine,
1,2,3,4-Tetrahydro-N-(2-hydroxyethyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-sulfonamide,
5-[(3-Methoxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,
5-[(3-Hydroxyphenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,
5-[(3-Hydroxyphenyl)sulfinyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,
5-[(3-Hydroxyphenyl)sulfonyl]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione,
3-Methyl-1-(2-methylpropy)-6-(1-naphthalenylmethyl)-5-[(3-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
5-[(3-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
5-{[3-{(Bis-methanesulfonyl)amino}phenyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
5-[(3-Methoxycarbonylaminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
5-[(3-Acetamidophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(4-nitrophenyl)thio]thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
5-[(4-Aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-5-[(5-nitropyridin-2-yl)thio]thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
2-{[1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]thio}pyridine N-oxide,
5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
5-[(3-Aminopropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}acetamide,
N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-Nxe2x80x2,Nxe2x80x2-dimethylurea,
N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}-methoxyacetamide,
Methyl N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}carbamate,
N-{3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}methanesulfonamide,
N-{(3-[(1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)thio]propyl}trifluoromethanesulfonamide,
5-{[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)propyl]thio}-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
N-(2-Hydroxyethyl)-Nxe2x80x2-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)]urea,
2-Hydroxyethyl [1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbamate,
N-(2-Hydroxyethyl)-N-methyl-Nxe2x80x2-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)]urea,
6-[(1-Hydroxy-1-(3-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
6-[(3-Fluorophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
6-[(1-Hydroxy-1-(2-bromophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-(2-methylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-(3-cyanophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-(3-trifluoromethylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-(3-phenyloxyphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-(1-naphthalenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-[(1-Hydroxy-1-(6-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-[(1-Hydroxy-1-(4-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
(xc2x1) 6-[1-(Benzo[b]furan-2-yl)-1-hydroxymethyl]-3-methyl-1-(2-methylpropyl))thieno [2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-[(1-Hydroxy-1-(2-chloro-6-fluorophenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno-[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-phenyl)ethyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-[(1-Hydroxy-1-(4-trifluoromethylphenyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
(xc2x1) 6-(2,3-dihydro-1-hydroxy-1H-indenyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-[(1-Hydroxy-1-(2-quinolinyl))methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-(1-Hydroxy-1-[3-quinolinyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-(2-bromophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-(2-methylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-(3-cyanophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-(3-trifluoromethylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-(3-phenyloxyphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(4-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(6-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(2-quinolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, trifluoroacetic acid salt,
6-(2-Benzo[b]furanylmethyl)-3-methyl-1-(2-methylpropyl)-)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-(2-Chloro-6-fluorophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
6-(1-Phenylethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H) -dione,
6-(4-Trifluoromethylphenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
(xc2x1) 6-(2,3-dihydro-1H-inden-1-yl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-(3-Imino-1,3-dihydro-benzo[c]furan-1-yl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione,
2-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]benzamide,
(xc2x1) 6-(1-Hydroxy-1-[1-naphthalenyl]methyl)-5-([3-hydroxypropyl]thio)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
3-Methyl-1-(2-methylpropyl)-6-(1-naphthalenylcarbonyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
(xc2x1)-5-[(3-Hydroxybutyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
6-(3-Fluorophenyl)methyl-5-[(3-hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
5-[(5-Amino-2-pyridinyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione,
Ethyl 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylate,
1,2,3,4-Tetrahydro-3,N,N-trimethyl-1-(2-methylpropyl)-6-phenylmethyl-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxamide,
6-[1-Hydroxy-(4-nitrophenyl)methyl]-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H, 3H)-dione,
6-(4-Nitrophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione,
6-(4-Aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione,
4-(3,4-Dimethoxyphenyl)-N-{4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl}-butanamide, and
3-Acetamido-N-(4-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl)methyl]phenyl)benzamide.
According to the invention there is also provided a process for the preparation of a compound of formula (I) which comprises:
(a) preparation of a compound of formula (I) wherein X is SO2, by oxidation of a compound of formula (I) wherein X is S(O)n and n is 0 or 1, in the presence of an appropriate oxidising agent (e.g. 3-chloroperoxybenzoic acid) and an appropriate solvent (e.g. dichloromethane) for example at 0xc2x0 C. to ambient temperature (20xc2x0 C.); or
(b) preparation of a compound of formula (I) wherein X is SO, by oxidation of a compound of formula (I) wherein X is S, in the presence of an appropriate quantity of a suitable oxidising agent (e.g. potassium peroxymonosulphate, commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d) in a suitable solvent (e.g. aqueous methanol), for example, at ambient temperature; or
(c) preparation of a compound of a formula (I) wherein X is S, by reacting a compound of general formula 
wherein R, R1 and R2 are as hereinbefore defined, with a compound of general formula (III), R17xe2x80x94Sxe2x80x94Sxe2x80x94R17, wherein the groups R17 both represent R9 or Ar3 as previously defined, or with a compound of general formula (IV), Lxe2x80x94Sxe2x80x94R17, wherein L represents a leaving group such as an arylsulphinate group and R17 is as defined above, in the presence of lithium diisopropylamide at a temperature from xe2x88x9278xc2x0 C. to 50xc2x0 C.; or
(d) preparation of a compound of formula (I) wherein R3 represents H, by reaction of a compound of general formula 
wherein R18 and R19 each independently represent an alkyl (e.g. ethyl) or aryl group and R and R1 are as hereinbefore defined, with a compound of general formula (VI), R2NH2, wherein R2 is as hereinbefore defined, in the presence of a suitable solvent (e.g. ethanol), for example, at elevated temperature and pressure; or
(e) preparation of a compound of formula (I) wherein X is C(O)NR10, by reacting a compound of general formula 
wherein R, R1 and R2 are as hereinbefore defined, with a compound of general formula 
wherein R9 and R10 are as hereinbefore defined, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole hydrate;
(f) preparation of a compound of formula (I) wherein X is NH(CO)NR10, by reacting a compound of general formula 
wherein R, R1 and R2 are as hereinbefore defined, with a compound of formula (VI) as described above, in the presence of a solvent such as toluene; or
(g) preparation of a compound of formula (I) wherein X is NH(CO)O, by reacting a compound of formula (IX) as defined above, with a compound of general formula (X), R9OH, wherein R9 is as hereinbefore defined, in the presence of a solvent such as toluene; or
(h) preparation of a compound of formula (I) wherein X is SO2NR10, by reacting a compound of general formula 
wherein L1 represents a leaving group such as a halogen atom (e.g. chlorine) and R, R1 and R2 are as hereinbefore defined, with a compound of formula (VIII) as defined above, in the presence of a solvent such as dichloromethane; or
(i) preparation of a compound of formula (I) wherein X is C(O)O, by reacting a compound of general formula 
wherein R3xe2x80x2 represents CO2R9 or CO2Ar3 and R, R1, R18 and R19 are as hereinbefore defined, with a compound of general formula (VI) as hereinbefore defined, in the presence of a suitable solvent (e.g. ethanol), for example, at elevated temperature and pressure;
and optionally after (a), (b), (c), (d), (e), (f), (g), (h) or (i) converting the compound of formula (I) obtained to a further compound of formula (I) and/or forming a pharmaceutically-acceptable salt or solvate thereof.
Compounds of formula (II) in which R is xe2x80x94C(xe2x95x90O)Ar1 may conveniently be prepared by reacting a compound of general formula 
in which R1 and R2 are as hereinbefore defined, with a compound of general formula (XIII), Ar1COCl, in the presence of aluminium (E) chloride and a solvent such as 1,2-dichloroethane under reflux conditions; or, alternatively, by oxidising a compound of general formula 
in which R4 represents H, R5 represents OH and R1 and R2 are as previously defined, in the presence of potassium permanganate and 1,4,7,10,13,16-hexaoxacyclooctadecane (commercially sold as xe2x80x9c18-Crown-6xe2x80x9d) in a solvent such as dichloromethane at ambient temperature.
Compounds of formula (XIV) in which R5 is OH and R1, R2, R4 and Ar1 are as hereinbefore defined may be prepared by reacting a compound of formula (XII) as defined above with a to compound of general formula 
in which R4 is as hereinbefore defined in the presence of lithium diisopropylamide at a temperature from xe2x88x9278xc2x0 C. to 50xc2x0 C.
Compounds of formula (XIV) in which R5 is H and R1, R2, R4 and Ar1 are as hereinbefore defined may be readily prepared by reducing a corresponding compound of formula (XIV) in which R5 is OH in the presence of triethylsilane and trifluoroacetic acid at ambient temperature.
Compounds of formula (II) in which R is Ar2 can be prepared by reacting a compound of formula (XII) as hereinbefore defined with 1-indanone, 2-indanone, 9-fluoreneone or 1-acenapthenone in the presence of lithium diisopropylamide and optionally cerium (E) chloride at xe2x88x9278xc2x0 C. to 50xc2x0 C. temperature, followed by a reduction reaction, e.g. in the presence of triethylsilane and trifluoroacetic acid.
Compounds of formula (V) may conveniently be prepared by reacting a compound of general formula 
wherein R, R1 and R18 are as hereinbefore defined, with a compound of general formula 
wherein R19 is as hereinbefore defined and Hal is a halogen atom (e.g. chlorine), in the presence of a suitable base (e.g. triethylamine) and a solvent such as dichloromethane.
Compounds of formula (XVI) in which R1 is H may be prepared by reacting a compound of general formula (XVEm), Rxe2x80x94CH2CHO, wherein R is as previously defined, with a compound of general formula 
wherein R18 is as previously defined, and with elemental sulfur, in a suitable solvent, e.g. dimethylformamide.
Compounds of formula (XVI) in which R1 is CH2C1-5 alkyl, CH2C2-5 alkenyl or CH2C3-5cycloalkyl may suitably be prepared by reacting a corresponding compound of formula (XVI) in which R1 is H, with a compound of general formula (XX), R20CO2H, wherein R20 represents C1-5 alkyl, C2-5 alkenyl or C3-5 cycloalkyl, and with a reducing agent such as sodium borohydride, in the absence of a solvent.
Compounds of formula (XVI) in which R1 is C1-6 alkyl or C3-6 cycloalkyl may conveniently be prepared by reacting a corresponding compound of formula (XVI) in which R1 is H, in the presence of a solvent such as toluene and catalytic toluenesulphonic acid under reflux conditions, with a compound of general formula 
wherein the groups R21 are both methyl or ethyl groups, and R22 and R23 each independently represent a hydrogen atom or an alkyl group or together form a hydrocarbyl ring, the total number of carbon atoms in R22 and R23 taken together not exceeding five, followed by reaction with a reducing agent such as sodium borohydride.
Compounds of formula (Va) may be prepared in a similar manner to the compounds of formula (V) but using in place of the compound of formula (XVI), a compound of general formula 
in which R, R1, R3xe2x80x2 and R18 are as previously defined.
Compounds of formula (XXII) in which R1 is H may be prepared by reacting a compound of general formula (XXIII), RCH2C(O)R3xe2x80x2, wherein R and R3xe2x80x2 are as previously defined, with a compound of formula (XIX) as hereinbefore defined and also with elemental sulfur in a suitable solvent.
Compounds of formula (XXII) in which R1 is other than hydrogen may be prepared by processes analogous to those described above for the preparation of compounds of formula (XVI) in which R1 is other than hydrogen.
Compounds of formula (VII) may suitably be prepared by reacting a compound of formula (II) above with carbon dioxide in the presence of lithium diisopropylamide, e.g. in tetrahydrofuran at a temperature from xe2x88x9278xc2x0 C. to 50xc2x0 C. under pressure.
Compounds of formula (IX) may be easily prepared by reacting a compound of formula (VII) as described above with diphenylphosphoryl azide, (C6H5O)2P(O)N3, in the presence of a solvent, e.g. a mixture of triethylamine and toluene.
Compounds of formula (XI) in which L1 represents a halogen atom such as chlorine can be prepared by reacting a compound of formula (II) as defined above with lithium diisopropylamide and sulfur dioxide to form an intermediate which is then further reacted with N-chlorosuccinimide and aqueous hydrochloric acid, in the presence of a solvent such as dichloromethane.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) where Ar3 is nitrophenyl can be converted to compounds of formula (I) where Ar3 is aminophenyl by reduction using iron powder and ammonium chloride in ethanol under reflux conditions; or compounds of formula (I) where Ar3 is pyridyl can be converted to compounds of formula (I) where Ar3 is pyridine N-oxide by reaction with 3-chloroperoxybenzoic acid in a solvent such as dichloromethane.
Compounds of formula (III), (IV), (VI), (VII), (X), (XII), (XIII), (XV), (XVII), (XVIII), (XIX), (XX), (XXI) and (XXIII) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
It will be appreciated by those skilled in the art that in the processes described above the functional groups (e.g. hydroxy, amino or carboxyl groups) of intermediate compounds may need to be protected by protecting groups. The final stage in the preparation of the compounds of the invention may involve the removal of one or more protecting groups. The protection and deprotection of functional groups is fully described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973), and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically-acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Isomers may be resolved or separated by conventional techniques, e.g. chromatography or fractional crystallisation. Enantiomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques (e.g. chiral HPLC). Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) or may be made with achiral starting materials and chiral reagents. All stereoisomers are included within the scope of the invention.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
The compounds of the invention are useful because they possess pharmacological activity in human and non-human animals. They are therefore indicated as pharmaceuticals for use in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS). Examples of these conditions are:
(1) (the respiratory tract) reversible obstructive airways diseases including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer""s lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter""s disease), Behcet""s disease, Sjogren""s syndrome and systemic sclerosis;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
The compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic micro-organisms.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
The invention further provides a method of effecting immunosuppression which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined.
The invention still further provides a method of treating, or reducing the risk of, a reversible obstructive airways disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compounds of formula (I) and pharmaceutically-acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99%w (per cent by weight), more preferably less than 80%w, e.g. from 0.10 to 70%w, and even more preferably less than 50%w, of active ingredient, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically-acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically-acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The invention will be illustrated by the subsequent examples in which the following abbreviations are used: m.p.=melting point, NMR=nuclear magnetic resonance, MS=mass spectrometry and h=hour(s).